Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review

Background This systematic study aims to assess the global epidemiologic, economic, and humanistic burden of illness associated with all types of hereditary angioedema. Methods A systematic search for articles reporting the epidemiologic, economic, and humanistic burden associated with patients with HAE was conducted using English and Chinese literature databases from the inception to May 23, 2022. The selected studies were assessed for their quality and risk of bias. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377). Results In total, 65 articles that met the search inclusion criteria reported 10,310 patients with HAE, of whom 5861 were female patients. Altogether, 4312 patients (81%) and 479 patients (9%) had type 1 and type 2 HAE, respectively, whereas 422 patients (8%) had HAE-normal C1-INH. The overall prevalence of all types of HAE was between 0.13 and 1.6 cases per 100,000. The mean or median delay from the first onset of a symptom of HAE to confirmed diagnosis ranged from 3.9 to 26 years. The estimated risk of death from asphyxiation was 8.6% for patients with HAE. Hospitalization, medication, unnecessary surgeries, doctor visits, specialist services, and nursing costs are direct expenses that contribute to the growing economic burden. The indirect cost accounted mostly due to missing work ($3402/year) and loss of productivity ($5750/year). Furthermore, impairment of QoL as reported by patient-reported outcomes was observed. QoL measures identified depression, anxiety, and stress to be the most common symptoms for adult patients and children. Conclusion This study highlights the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-024-03265-z.


Introduction
Hereditary angioedema (HAE) is a rare, debilitating, lifethreatening genetic disorder characterized by recurrent attacks of subcutaneous and/or submucosal angioedema [1].Several forms of HAE have been defined based on gene mutations: (1) type 1 HAE identified as C1 inhibitor (C1-INH) deficiency with low levels of C1-INH; (2) type 2 HAE identified as C1-INH dysfunction with normal or slightly increased levels of C1-INH but low functional levels, both type 1 and type 2 are due to mutations of the serine protease inhibitor gene 1 (SERPING1); and (3) HAE with normal C1-INH levels (HAE-nC1-INH) including (a) mutations of FXII gene (HAE-FXII), (b) HAE with a mutation in the angiopoietin-1 gene (HAE-ANGPT1), (c) HAE with a mutation in the plasminogen gene (HAE-PLG), (d) HAE with a mutation in the kininogen 1 gene (HAE-KNG1), (e) HAE with a mutation in the myoferlin gene (HAE-MYOF), and (f ) HAE with a mutation in the heparan sulfate 3-O-sulfotransferase 6 gene (HAE-HS3ST6); some patients have HAE due to unknown mutations identified as HAE-UNK [2].C1-INH is an inhibitor of plasma kallikrein and factor XII that are responsible for the generation of bradykinin.An increase in the levels of bradykinin causes extravasation of plasma, which leads to painful swelling.In cases of larynx angioedema, it could be life-threatening to the patients [2].
Hereditary angioedema accounts for approximately 2% of clinical angioedema cases [3].Although the global prevalence of HAE is estimated at 1:50,000, the true prevalence of HAE remains unclear because the disease is rare [4].Furthermore, according to the epidemiologic reports, the prevalence of type 1 HAE is observed in the majority of patients (80%-85%), whereas type 2 HAE is present in 15% to 20% of patients [5][6][7][8].HAE-nC1-INH is only accounted for by a minor proportion of patients [9].An earlier study has observed no major gender or ethnic differences in the HAE type 1/2 [4][5][6][7]10].However, an analysis reported that HAE-nC1-INH is exclusive to women and postulated it to be related to X-linked dominant mode of inheritance [11].Likewise, HAE-FXII and HAE-unknown were more pronounced in females with a male to female ration of 1:68 and 1:6.3, respectively [12].The onset of HAE symptoms varies by age and can occur in children aged < 1 year, with the development of laryngeal attacks occurring usually after the age of 3 years with an increased frequency observed after puberty [13].
Patients with HAE had angioedema attacks including pain and swelling at the extremities, abdomen, genitourinary tract, face, or oropharynx and any other possible site.More often, because of the overlap of clinical symptoms between various forms of angioedema or with other systemic diseases, and the relatively rare of it, HAE remains underreported or misdiagnosed.Consequently, there is a considerable delay in the accurate diagnosis of HAE from the onset of symptoms [1].This may lead to unnecessary treatments and surgeries further delaying the timely treatment of HAE, which may contribute to a substantial burden in patients with HAE.
HAE attacks are usually variable as well as unpredictable and might be induced by various stimuli.The empirical triggering factors include stress, physical exertion, trauma, infection, hormonal changes, medical interventions, seasonal changes, and the use of certain medicinal products [14].On average, the frequency of attacks ranges from 1 to 26 per year [10,15].But in rare cases, patients have reported 100 attacks per year, which may last up to 5 days [16].The unpredictability of angioedema attacks, high risk of asphyxia, and the need for emergency intervention often result in a significant burden for patients with C1-INH-HAE [17].Moreover, the above factors adversely affect the patients' health-related quality of life (HRQoL) and increase the economic burden.
Many efforts have been taken to quantify the epidemiologic, economic, and humanistic burden of this disease, but the poor comparability between the studies has limited the detection of common issues and real differences.To address this gap, we sought to systematically synthesize the evidence on the epidemiologic, economic, and humanistic burden associated with HAE.

Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377).

Search Strategy
We searched English and Chinese databases for articles related to the epidemiologic, humanistic, and economic burden associated with HAE published from the inception of respective databases until May 23, 2022.The following search terms were used for conducting literature searches: "hereditary angioedema, " "HAE, " "epidemiology, " "prevalence, " "incidence, " "mortality, " "death rate, " "fatality, " "burden of disease, " "healthcare resource utilization, " "cost of illness, " "cost, " "productivity, " "economic, " "economic burden, " "healthcare costs, " "hospitalization, " "direct cost, " "indirect cost, " "quality of life, " "Health-Related Quality Of Life, " "Life Quality, " "activities of daily living, " "patient satisfaction, " "caregiver burden, " "impact of burden, " and "quality adjusted life year." The search strategies for each database and review process are detailed in the Supplementary file.

Inclusion and exclusion criteria
We included (1) studies with patients suffering from HAE; (2) studies with the following outcomes (a) epidemiology (prevalence, incidence, mortality rates, and diagnosis delay), (b) economic burden (health resource utilization, direct and indirect cost, inpatient and outpatient visit expenses, family care cost, hospitalization cost, and financial burden cost), or (c) humanistic burden (HRQoL measurements with different tools, disability-adjusted life year [DALY], activities of daily living [ADL], quality-adjusted life-year [QALY], patient satisfaction, and caregiver burden); (3) observational studies (prospective and retrospective cohort studies, cross-sectional studies, and case-control studies) and experimental studies (randomized controlled trials [RCTs], single-arm or nonrandomized controlled trials, and cluster trials); and (4) studies that have been published in English or Chinese databases from the inception to May 23, 2022.Studies that reported costs or cost-effectiveness associated with specific treatments of HAE and consisted of study designs, comments, study protocol, editorials, review articles, case reports, and case series were excluded.

Study selection
The preliminary screening was conducted based on the title and abstracts according to the predefined eligibility criteria.The full texts of the included articles were further reviewed and examined for relevant outcome as aligned with the eligibility criteria.A full-text screening was conducted independently by 2 researchers, and any disagreements between the reviewers were resolved by discussing with the third independent reviewer.

Data extraction and quality assessment
Information from the included articles was extracted into a standardized MS Office Excel table.Data related to the author, year of publication, title, study design, demographics of the study population, and outcomes of interest were extracted by 2 independent reviewers with the quality check performed by the third reviewer.Although statistical analysis was not planned, the results were narratively synthesized to identify the common themes and gaps in the evidence.The methodological quality of eligible nonrandomized studies was determined using the Newcastle-Ottawa scale (NOS).The NOS consists of 3 quality parameters with a total of 9 points.Studies with an NOS score of > 6 were considered high-quality studies [18].

Diagnosed prevalence of HAE
As reported in 8 studies, the prevalence of HAE ranged between 0.13 and 1.6 cases per 100,000 (Table 1).The prevalence rates were low across all included studies.In Sweden, the estimated prevalence rates for 2011 and 2016 were 1.5 and 1.6 cases per 100,000, respectively [54,55].In South Korea, the prevalence was 0.13 cases per 100,000 [33], whereas in Denmark and Austria, the estimated prevalence was 1.4 and 1.6 cases per 100,000, respectively [31,44].Similarly, the estimated prevalence rates in Belarus, South Africa, and the US were between 0.7 and 1.0 cases per 100,000 [21,34,47].A study conducted in the US simultaneously reported the prevalence of HAE among ethnic groups.The prevalence of HAE in Black patients (1.64 cases per 100,000) was almost similar to that of White patients (1.47 cases per 100,000), whereas it was lower among Hispanic patients (0.80 cases per 100,000) [47].Furthermore, according to a study conducted in Tongji Hospital in China, the prevalence of HAE was reported to be 2.43 cases per 10,000 in patients with decreased complement 4 level [19].

Risk of death in patients with HAE
One study reported a low age-adjusted mortality (the ratio of the number of deaths in a specified time to a given population) of 0.17 (95% CI, 0.15-0.18)per million persons per year for HAE in the US [39].Additional 9 studies reported 124 deaths caused by asphyxiation (due to laryngeal edema) among 1440 patients, which leads to an estimated 8.6% of risk of death from asphyxiation for patients with HAE.One of the 9 studies reported the lifespan of patients with undiagnosed HAE type 1/2 who died of asphyxiation was shorter than that of patients with undiagnosed HAE type 1/2 who died of other causes (40.8 years vs 72.0 years) [42].Furthermore, a descriptive epidemiologic study conducted in the US evaluated the death among all HAE hospitalizations and HAE-related hospitalizations [66].The study observed that 145 deaths occurred during all HAE hospitalizations (n = 10,125) and 9 deaths occurred during 3216 HAE-related hospitalizations (Table 1).

Diagnosis of HAE
The delay in diagnosis was reported by 34 studies with the mean or median range of 3.9 to 26 years from the first onset of HAE symptoms to the confirmed diagnosis (Table 1).In 25 articles, the mean or median delay was reported to be > 10 years, indicating there was a widespread misdiagnosis of HAE globally.One of the studies found that patients without family history had a longer delay than those with family history (6.0 years vs -0.9 years) [38], whereas another study found that the delay in diagnosis was shorter in patients with HAE type 1 than those with HAE type 2 (10 years vs 18 years) [64].

Economic burden
Direct costs associated with HAE were reported in 6 studies, which assessed the treatment costs and health care utilization (Table 2).The major components accounting for the increase in economic costs were hospitalization, treatments, unnecessary surgeries, doctors' visits, specialist services, and nurse costs.Three studies conducted in the US estimated the hospital costs to be $17,335 per year and about $4000 for a single hospitalization [56, 65, [59,67].Twelve studies reported indirect economic burden that included various productivity measures (Table 3).Among them, absenteeism from work was 5.9% to 31.1% because of HAE attacks.The presenteeism among patients who were physically present at work was approximately 20%, ranging from 10% to 24.6%.Furthermore, Wilson et al. reported a loss of $5750 because of decreased productivity at work affecting income.In addition, the study also reported the loss of wages for missed work because of a single attack approximated to be $525.Therefore, missed   work because of acute attacks resulted in an income loss of $3402 annually, and for chronic disease management, the income was reduced to almost $6512 because of working fewer hours as compared with working full time [67].There was variation in the number of days missing from work/school because of different time duration.In general, the average number of missed days in 1 year was between 1.7 and 19.9 days, and in total, the indirect cost was $16,108 annually.

Humanistic burden
The quality of life (QoL) was reported in a total of 23 publications.In 9 studies, the most frequently used measure to assess the HRQoL for patient-reported outcome  4 lists the summary of studies reporting humanistic burden in HAE.
The mean overall summary scores for the physical component summary (PCS) in the SF-36 survey ranged from 40.9 to 49.8 and for the mental component summary (MCS) ranged from 41.6 to 50.4.Three studies from Brazil, Portugal, and Denmark reported the mean scores of 8 domains of SF-36 ranging from 51.0 to 76.0, 49.2 to 83.2, and 62.8 to 92.9 [77][78][79], respectively.The mean scores in at least 1 dimension were significantly lower for the HAE population compared with the normal population in 5 studies [53,57,71,72,76], whereas another 2 studies reported that patients with HAE had QoL scores similar to the reference population [78,79].Three studies reported the scores of the PCS and MCS in the SF-12 survey, ranging from 43.7 to 49.26 and 42.6 to 44.9, respectively [51,52,60].Nordenfelt et al. evaluated the utility of EQ-5D to describe the current health state and the state during their most recent HAE attack, which indicated an impaired HRQoL for patients with HAE both during and between attacks [55].Another 2 studies that measured the HRQoL using EQ-5D demonstrated an impairment of QoL as well, with a health utility of 0.7 for French patients and of 0.8 for Swedish patients [54,59].The scores of VAS were reported in 2 studies with the value of 80.0 for adult patients and 86.0 for pediatric patients [54,74].
A disease-specific questionnaire such as AE-QoL was also used to assess the impact of angioedema on daily life for 4 weeks before answering the questionnaires.The instrument involved a 17-item questionnaire assessing the impairment of HRQoL from 4 dimensions (functioning, fatigue/mood, fears/shame, and nutrition), and a higher score indicated the severity of impaired HRQoL.The AE-QoL scores in 4 studies varied from 20.6 to 47.1.HAE-QoL, another 25-item disease-specific questionnaire, assessed the extent to which angioedema has affected daily life for the last 6 months from 7 dimensions (treatment difficulties, physical functioning and health, disease-related stigma, emotional role and social functioning, concern about offspring, perceived control over illness, and mental health), with the higher score representing better HRQoL.The mean scores of the included studies ranged from 93.1 to 102.Nunes et al. showed substantial improvement in HAE-QoL scores at 8 and 14 months compared with baseline because of a systematic intervention (Δ score: 15.2 at 8 months; Δ score: 26.0 at 14 months) [58].
Peds-QL is the most frequently used tool to evaluate the HRQoL in pediatric patients with HAE, with a higher total score indicating a better HRQoL.Two of the 3 studies measured using Peds-QL demonstrated a lower HRQoL for pediatric patients with HAE than healthy children [73,75], whereas the third study observed comparable HRQoL scores for pediatric patients with HAE type 1/2 with normal scores for healthy children [74].Aabom et al. developed a nonvalidated, disease-specific tool using Peds-QL as a structural model to measure the impact of HAE on pediatric patients, with a score of 5.6 ± 10.0.The CDLQI designed to measure physical discomfort, social discomfort, and activity limitation showed a CDLQI score of 2.0 ± 5.9 for pediatric patients [74].
Depression, anxiety, stress, and alexithymia are the most common symptoms for both adult patients and children as proved by DASS-21, PSS, HDI-SF, HDRS, STAIC, TAS, and ERC (see Table 4).Another uncommon instrument has been used to report the QoL in the studies.The RAND-36 is a generic instrument (similar to SF-36) evaluating the HRQoL from 9 dimensions, with 0 for the worst and 100 for the best.Nordenfelt et al. reported median scores of 9 dimensions of RAND-36 ranging from 50 to 100 [54].

Discussion
To the best of our knowledge, this systematic review is the first to provide a comprehensive understanding of the epidemiologic, economic, and humanistic burden of HAE.This review indicates that HAE is associated with a substantial burden and will undoubtedly become more pronounced with rising awareness of the disease globally.At present, because of rarity and limited symptom specificity, HAE is indeed often misdiagnosed, leading to a significant delay (> 10 years) in correct diagnosis.Besides, a lack of awareness among health care professionals, limited availability of diagnostic tests, and incorrect treatment restrict the timely and optimal management of HAE [80,81].As a result, it has been found that 8.6% of patients with HAE have experienced laryngeal edema, which has led to death caused by asphyxiation.These concerning statistics emphasize the critical need for early diagnosis and increased awareness of the disease.The HRQoL is the patients' perception regarding the multidimensional impact of the disease [82].Evidence from this review illustrates the negative impact of HAE on the QoL.Twenty-three studies assessed the burden of HAE on the QoL of patients; however, only 3 reported QoL of children aged 2 to 18 years with HAE highlighting a significant knowledge gap [73][74][75].In this study, we observed that most patients were provided with an SF-12/SF-36 survey questionnaire or an HAE-QOL/AE-QOL questionnaire.The majority of the studies showed poorer PCS and MCS in patients with HAE relative to the control.There was a significant association of psychological implications such as anxiety and depression with HAE identified by either high score values on rating scales or during conversations with the participants [83].HAE had a significant negative impact on the QoL both during and between attacks that reflected on absenteeism at work or school [55].The World Allergy Organization guidelines about C1-INH-HAE suggest considering the HRQoL when determining maintenance treatment, and HAE experts advise to assess the HRQoL annually [2,84].Data derived from large populations are necessary to accurately measure the HRQoL in patients with C1-INH-HAE, its trigger factors, and the effects of therapeutic interventions.
To our knowledge, only 2 studies from the US and France have estimated the economic burden associated with HAE.Although the evidence is sparse, the present review identified hospitalization cost, medication cost, and other procedural costs such as surgery, physician visits, and nursing services ($1000-$3510 among the US patients and €135 among French patients with HAE) to be the main components of direct costs, whereas outpatient visits and other outpatient services ($189) were the minimal components of economic burden as reported in the included studies [59,67].Economic assessments of HAE indicated decreased work productivity because of disease burden added to the indirect costs.The loss of income because of reduced productivity was $5750 per patient per year as reported by Wilson et al. and lost wages for missed work because of a single attack was estimated to be ~ $525; conversely, the lost wages per annum would be ~ $3402; and the reduction in income because of absenteeism was ~ $6512 [67].These estimates indicate a considerable economic burden associated with HAE ascertaining the need to prevent functional limitation and improving the QoL for patients is vital in reducing absenteeism.
Meanwhile, there was a huge variation in the reported data pertaining to the cost; few studies provided a detailed breakdown of direct and indirect costs, whereas other studies described only major cost categories, which limited the comparisons between studies.Finally, variability in outcome measures was observed across studies.The study heterogeneity in terms of patient characteristics and study setting (eg, recruitment at secondary or tertiary clinics and claims databases) across the included articles may have contributed to the wide ranges of the observed data in the results.Future studies using standardized approaches to conduct and report the burden of illness would reduce this data heterogeneity and enable better burden comparisons between studies.With the approval of new drugs for HAE globally, there is an urgent need to determine the direct medical costs incurred by patients using these drugs.

Conclusion
The lack of comprehensive epidemiologic data on the incidence of HAE creates a knowledge gap regarding the true overall burden of HAE on society.However, there is considerable evidence indicating that delayed diagnosis of HAE is associated with decreased physical function, increased risk of mortality, negative psychological impact, and higher direct and indirect costs.This review compiles evidence highlighting the need for early diagnosis, improved disease management, and increased awareness among health care professionals to mitigate the excessive burden on patients.

Table 1
Key characteristics of included studies

Table 2
Direct costs related to HAE Abbreviations: ED Emergency department, GP General physician, HAE Hereditary angioedema, PD Principal diagnosis

Table 3
Indirect economic burden of HAE

Table 4
Humanistic burden in HAE

Table 4
(continued) ERC, Emotion Regulation Checklist, the mean values for both males and females within the normative samples can be referred as cut-off values for the index.HADS, Hospital Anxiety and Depression Scale, anxiety and depression subscale scores range from 0 to 21, 0-7 = Normal, 8-10 = mild, 11-14=moderate, 15: severe psychological morbidity.HDRS, Hamilton Depression Rating Scale, higher values correlate with more severe depressive symptoms.Peds-QL, Pediatric Quality of Life, 0-100-point scale, a higher total score indicates a better HRQoL.PSS, Perceived Stress Scale, a 10-item self-reported scale, measures the degree to which situations in one's life are appraised as stressful.Stress was assessed as low with a score < 13, moderate with a score of 14-26, and as highly perceived when the score was > 27.RAND-36, Research and Development, average score between 0 (worst) and 100 (best), a higher total score indicates a better HRQoL.SF-36, 36-item Short Form; average score between 0-100, a higher total score indicates a better HRQoL.SF-12, 12-Item Short Form Health Survey, scores range from 0 to 100 with higher score indicating better physical and mental health.STAIC, State-Trait Anxiety Inventory for Children, total scores for state and trait range from 20 -80, higher scores indicate greater anxiety.TAS, Toronto Alexithymia Scale, a 20-item self-reported questionnaire which evaluates alexithymia, the difficulty in recognizing and naming and describing one's own emotions.A score of < 51 indicates absence of alexithymia, a score of 52-60 indicates a possible alexithymia, and a score of > 61 indicates alexithymia.EQ-5D, The EuroQol 5 Dimension, range 0-1, higher scores reflect better health.VAS, Visual Analogue Scale, 0-100, higher scores reflect better general health.HDI-SF, the range of score is 0-33, with higher scores indicating more depression symptom.nonvalidated tool, range 0-52, higher scores reflect more impaired HRQoL HAE Hereditary angioedema, MCS Mental component summary score, PCS Physical component score, QoL Quality of life, ERF Emotional role functioning, SF Social functioning, GH General health, BP Bodily pain, PRF Physical role functioning